Rickettsia rickettsii causes Rocky Mountain spotted fever (RMSF), a significant public health threat with the highest fatality rate of any tick-borne disease in the United States. In the western U.S., RMSF occurs in highly focal zones where it is transmitted principally by the bite of wood ticks (Dermacentor andersoni). A better understanding of the factors regulating transmission and maintenance of R. rickettsii by its tick host and vector will offer insight on the mechanisms infectious bacteria employ to naturally maintain themselves and ultimately emerge as human pathogens. Our laboratory investigations were aimed at evaluating intrinsic factors which either limit the transmission of R. rickettsii or enhance it to result in focal epizootics. The principal factors include: 1) endogenous tick-borne agents, 2) pathogenic effect of R. rickettsii on the tick vector, and 3) reactivation of overwintering R. rickettsii. First, the role of endogenous tick agents on the transmission of R. rickettsii was studied. Investigations on the capacity of R. peacockii, a symbiotic bacteria found in approximately 70 % of wood ticks from an area devoid of RMSF, to interfere with the natural maintenance of R. rickettsii were recently completed. Complete blockage of the virulent R. rickettsii was pinpointed and quantified. This is the first documented occurrence of a microorganism preventing the enzootic maintenance of a bacterial relative and the infectious disease it causes. Second, the capacity of a tick to successfully transmit R. rickettsii to humans and other vertebrates relies on the vector?s ability to acquire the pathogen and survive long enough to pass it on. For this reason, the pathogenicity of R. rickettsii for its principal vector was quantified. Recent laboratory trials indicate that R. rickettsii was lethal to a high percentage of wood ticks infected during blood feeding. In addition, ticks infected with R. rickettsii had a significantly lower fecundity as compared to uninfected siblings. This pernicious effect may partially explain the low incidence of R. rickettsii-infected ticks in the wild and limit the annual incidence of RMSF. These findings also imply that vertebrate hosts are required to amplify R. rickettsii and maintain the natural transmission cycle. Third, R. rickettsii overwinters within ticks as a nonvirulent bacterium yet undergoes a transformation during tick blood feeding that results in an infectious or reactivated bacterium. To help elucidate the mechanisms responsible for this poorly understood reactivation phenomenon, tests are being conducted to determine whether new proteins are synthesized by the bacterium or R. rickettsii undergoes rapid replication during reactivation. During these ongoing studies, we discovered that passage of virulent R. rickettsii in cell culture reduced its infectivity for both vertebrates and ticks. Identification of constituents associated with reactivation and virulence may provide insight on improved detection and prevention of RMSF and other emerging infectious diseases.